tbuckley/cabot-search huggingface dataset:
Abstract 2957: Inhibition of epigenetic regulator menin is a novel therapeutic approach for high-risk neuroblastoma
Authors: Rameswari Chilamakuri, Saurabh Agarwal
Journal: Cancer Research (2022)

Abstract Controlling epigenetic factors such as histone methyltransferases and demethylases has recently emerged as an attractive therapeutic approach for different cancers. KMT2 family protein KMT2A or MLL1 is a H3K4 methyltransferase, which is known to play an essential role in cancer development. MLL1 forms a COMPASS complex to function as an epigenetic regulator and Menin is one of the specific and required binding partner for the activation and function of this epigenetic enzyme. Menin acts as a tumor suppressor protein, and inhibition of Menin-MLL1 interaction has been shown to destabilize the MLL1 epigenetic complex, inhibits H3K4 methyltransferase activity, and hinder the oncogenic potential of various cancers. High-risk neuroblastoma (NB) is the most common extracranial solid pediatric tumor and accounts for almost 15% of all pediatric cancer-related deaths. Recent reports indicate that aberrant activation of epigenetic regulators may drive NB progression and relapse. Therefore, in the present study, we used a specific small-molecule inhibitor, MI-503 to disrupt Menin-MLL1 interaction, and to further understand the role of Menin in pediatric NB. We used different NB cell lines including MYCN-non-amplified (SH-SY5Y, SK-N-AS, CHLA-255) and MYCN-amplified (NGP, LAN-5, IMR-32), and performed cytotoxicity and Colonogenic assays to determine the effect of Menin inhibition on NB proliferation. Results showed that MI-503 significantly inhibits NB proliferation and colony formation capacity in a dose-dependent manner in contrast to controls. Further, we performed apoptosis and cell cycle assays and observed that MI-503 significantly induces apoptosis as detected by the increase of Annexin-V positive early apoptotic cells, and blocks cell cycle progression at the S phase in all NB cell lines tested. Additionally, Western blot assays demonstrated an overall inhibition of H3K3me3 levels in NB cells in response to MI-503. To further determine the effects of Menin inhibition on NB tumor growth, we developed a NB 3D spheroid tumor model that recapitulate in vivo tumor growth for solid tumors. Treatment with MI-503 significantly inhibits spheroidal tumor growth by inducing tumor cell death in a dose-dependent manner. Overall, these data highlight the role of epigenetic regulation, MLL1 complex, and of Menin in NB growth and tumorigenicity. In our future efforts, we will further elucidate the effects of MI-503 and the role of Menin in NB by using in vivo tumor models. Epigenetic inhibitor such as MI-503 holds significant potential for further clinical development and as a novel therapeutic approach for NB. Citation Format: Rameswari Chilamakuri, Saurabh Agarwal. Inhibition of epigenetic regulator menin is a novel therapeutic approach for high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2957.
Abstract 5504: Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to restrain acquired resistance from antigen-loss-variant tumor cells
Authors: Yong Lu
Journal: Cancer Research (2022)

Abstract Adoptive cell therapy (ACT) with tumor-specific T cells expressing T-cell-receptors (TCR) or chimeric antigen receptors (CAR) has not mediated sustained responses in solid tumors. Several factors limit the efficacy of ACT in solid tumors and lead to primary resistance and acquired resistance (refers to recurrence after the initial response). These include but not limited to the insufficient proliferation of T cells, the low capacity of T cells to penetrate stroma-rich solid tumors, and heterogeneity of antigen expression in solid tumors, which allows the escape of T cell attack by tumor cells when becoming antigen-loss-variant cancer cell (ALV). Hence, it is urgent to develop novel ACT strategies to eradicate solid tumors and prevent acquired resistance. We have previously reported (Yong Lu, Cancer Cell, 2018) that tumor-specific IL-9-producing CD4+ Th9 cells represent a novel T cell paradigm for ACT - they are less exhausted, fully cytolytic, and hyperproliferative. This hyperproliferation of Th9 cells is driven by a unique Th9 master transcriptional factor Pu.1 mediated Pu.1-Traf6-NFκB signaling to ensure Th9 cells persist as long as “stem cell-like” T cells, which is not presented in other known CD4+ T cells subsets. In our most recent study, we demonstrate that murine and human Th9 cells, but not Th1/Tc1 or Th17 cells, expressing tumor-specific T-cell-receptors (TCR) or chimeric antigen receptors (CAR), eradicate advanced tumors that contain ALVs. This unprecedented antitumor capacity of Th9 cells is attributed to both enhanced direct tumor cell killing and bystander antitumor effects promoted by intratumor release of IFNα/β. Mechanistically, tumor-specific Th9 cells increase the intratumor accumulation of extracellular ATP (eATP, released from dying tumor cells), because of a unique feature of Th9 cells that lack the expression of ATP degrading ectoenzyme CD39. Intratumor enrichment of eATP promotes the monocyte infiltration and stimulates their production of IFNα/β by inducing eATP-endogenous retrovirus-TLR3/MAVS pathway activation. These results identify tumor-specific Th9 cells as a unique T cell subset endowed with the unprecedented capacity to eliminate ALVs for curative responses. Citation Format: Yong Lu. Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to restrain acquired resistance from antigen-loss-variant tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5504.
Abstract 5617: A novel genetically modified oncolytic vaccinia virus selectively replicates in tumors to activate an inflammatory TME and induce tumor regression
Authors: Anne-Laure Goenaga, I-Ming Wang, Bryan S. Clay, Susanne Lang, Annabel Wang, Peter Weady, Smitha P.S. Pillai, Sripad Ram, Leah Mitchell, Michael Eisenbraun, Joseph Binder, Liliana Maruri Avidal, David Kirn, Robert Hollingsworth, Clare Lees
Journal: Cancer Research (2022)

Abstract Oncolytic viruses (OVs) have been widely investigated as cancer immunotherapy platforms and are represented by a diverse group of DNA and RNA viruses. We are currently investigating a genetically modified oncolytic vaccinia virus as a best-in-class tumor-selective investigational product for the treatment of solid tumors. Specifically, the viral thymidine kinase (TK) has been deleted to enhance safety by greatly limiting replication in healthy tissues while taking advantage of relatively higher endogenous TK levels in tumors. In addition to tumor-selective replication, the oncolytic vaccinia virus encodes an IL-2 variant (IL-2v) protein, which diminishes preferential activation of immunosuppressive Treg cells while preserving activation of CD8+ and NK cells and avoiding toxicities associated with wild type IL-2. Using a murine surrogate of the oncolytic vaccinia virus, we assessed preclinical efficacy in multiple murine syngeneic tumor models demonstrating selective tumor localized replication resulting in tumor growth inhibition. Consistent with tumor selective virus replication, viral copy number and IL-2v transgene levels were increased and had prolonged expression in the tumors compared to the periphery. Intratumoral colocalization of the virus and IL-2v was confirmed by IHC and ISH, respectively. Tumor growth inhibition was associated with increases in tumor infiltrating CD8 and NK effector cells. Additionally, efficacy of the mouse surrogate virus was associated with systemic increases in circulating total CD8 and NK cells as well as pSTAT5+ CD8 and NK cells in the blood. In summary, we have demonstrated that arming a TK-deficient oncolytic vaccinia virus with an IL-2v transgene can effectively couple short-term destruction of tumor cells through oncolysis with the activation of anti-tumor immune response in the tumor microenvironment. These data support the study of this therapy in Phase 1 clinical trials. Citation Format: Anne-Laure Goenaga, I-Ming Wang, Bryan S. Clay, Susanne Lang, Annabel Wang, Peter Weady, Smitha P.S. Pillai, Sripad Ram, Leah Mitchell, Michael Eisenbraun, Joseph Binder, Liliana Maruri Avidal, David Kirn, Robert Hollingsworth, Clare Lees. A novel genetically modified oncolytic vaccinia virus selectively replicates in tumors to activate an inflammatory TME and induce tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5617.
Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer
Authors: Peter A. Fasching, Duan Liu, Steve Scully, James N. Ingle, Paulo C. Lyra, Brigitte Rack, Alexander Hein, Arif B. Ekici, Andre Reis, Andreas Schneeweiss, Hans Tesch, Tanja N. Fehm, Georg Heinrich, Matthias W. Beckmann, Matthias Ruebner, Hanna Huebner, Diether Lambrechts, Ebony Madden, Jess Shen, Jane Romm, Kim Doheny, Gregory D. Jenkins, Erin E. Carlson, Liang Li, Brooke L. Fridley, Julie M. Cunningham, Wolfgang Janni, Alvaro N.A. Monteiro, Daniel J. Schaid, Lothar Häberle, Richard M. Weinshilboum, Liewei Wang
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS). Experimental Design: A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes. Results: One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE. Conclusions: Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.
Abstract 433: Colorectal and gastric cancer screening rates in Korea during the COVID-19 pandemic
Authors: Seung Hee Seo, Hyeree Park, Jong Heon Park, Bhumsuk Keam, Shin Hye Yoo, Aesun Shin
Journal: Cancer Research (2022)

Abstract Background: The COVID-19 pandemic has disrupted healthcare delivery, which is widely discussed as the distraction effect. This study aimed to estimate the distraction effect of the COVID-19 pandemic in Korea by analyzing colorectal and gastric cancer screening rates in the years 2019 and 2020. Methods: Information of eligible population who had colorectal and gastric cancer screening provided by the National Cancer Screening Program in the years 2019 and 2020 was collected. Participation rates were analyzed by age group, sex, geographic region, and calendar month. Percentage change was calculated by dividing the percentage point difference by the screening rate of the reference period (2019). Results: Overall, the colorectal and gastric cancer screening rates had decreased in 2020, compared to the reference period. For colorectal cancer, the screening rate decreased from 68.3% in 2019 (5,886,319 participants/14,526,424 eligible population) to 54.6% in 2020 (5,135,218/9,410,525) For gastric cancer, the screening rates decreased from 61.9% in 2019 (7,194,489/11,625,627) to 54.6% in 2020 (6,244,491/11,439,246). In March, during the first wave, the screening rates declined sharply (percentage change: colorectal, 56.6%; gastric, 57.3%). Although the screening rates had rebounded aftermath, they declined again in December, during the third wave (percentage change: colorectal, 17.0%; gastric, 13.8%). According to specific-age group, we found a substantial decline in screening rates for older adults aged 80~84, and those over 85 (percentage change: colorectal, 19.0% &amp; 23.0%; gastric, 17.4% &amp; 25.1% respectively). Conclusion: During the COVID-19 pandemic, the screening rates for both colorectal and gastric cancer decreased. There was a substantial decline during the first and the third waves of the epidemic, in March and in December. The older adults group showed the highest reduction in screening rates. However, comparing the screening rate by region and sex, we did not find a significant difference. Delayed cancer diagnosis or excess death due to distraction effect of the COVID-19 pandemic has not yet been detected in Korea, therefore, further studies are needed. Citation Format: Seung Hee Seo, Hyeree Park, Jong Heon Park, Bhumsuk Keam, Shin Hye Yoo, Aesun Shin. Colorectal and gastric cancer screening rates in Korea during the COVID-19 pandemic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 433.
Abstract 5252: In colorectal cancer (CRC), neuroendocrine carcinoma (NEC) is contaminated in the cancer given a confirmed diagnosis of poorly differentiated adenocarcinoma (P-ad-ca)
Authors: Yuhan Rong, Yuma Takeda, Naoki Okubo, Akihiro Suzuki, Motohiko Tokuhisa, Noritoshi Kobayashi, Atsushi Ishibe, Ikuma Kato, Shoji Yamanaka, Satoshi Fujii, Itaru Endo, Yasushi Ichikawa
Journal: Cancer Research (2022)

Abstract Background: Most of CRC were well or moderately differentiated adenocarcinoma and P-ad-ca is very rare. In Japan, P-ad-ca was reported to be only 4-6% of all CRC. NEC is also rare. The incidence of that were reported to be less than 1%. One of their points of common is morphological poorly differentiated appearance. In this study, we evaluated the incidence of NEC contaminated in the CRC given a confirmed diagnosis as P-ad-ca. Material and Method: From 2009 to 2019, 816 CRCs were resected in department of Yokohama City University Hospital and 74 cases showing P-ad-ca or having a small region of P-ad-ca with well or moderately differentiated ad-ca (W-ad-ca, M-ad-ca). Among the 74 cases, there were 8 of P-ad-ca, 4 of W-ad-ca with P-ad-ca, 44 of M-ad-ca with P-ad-ca, and 18 W-ad-ca and M-ad-ca with P-ad-ca. Immunohistochemistry (IHC) using neuroendocrine markers (NM) including chromogranin A, synaptophysin and insulinoma-associated protein 1 (INSM1) was performed to identified NEC. Recently, a high incidence of Rb protein loss was reported in NEC of several organs, then IHC using Rb monoclonal antibody was also performed. The cancers showing immunohistochemically positive of at least one of the three NM and negative of Rb were identified as true NEC in this study. Results: At least one of the three NM was positive in the 39 cases. In these 39 cases, 3 cases were also Rb negative. Two of the three cases were region of P-ad-ca. These 2 P-ad-ca regions showed positive of NM. Interestingly, in the other one case, region of W-ad-ca showed positive of NM and negative of Rb. Region of P-ad-ca of the case showed positive of all three NM and Rb. From morphological appearance, this case was quite unlikely to true NEC. Conclusion: In 74 P-ad-ca, 2 cases might be true NEC in our small evaluation. NEC might be contaminated in the P-ad-ca of CRC which is difficult to be distinguished by only pathological findings of HE staining. Citation Format: Yuhan Rong, Yuma Takeda, Naoki Okubo, Akihiro Suzuki, Motohiko Tokuhisa, Noritoshi Kobayashi, Atsushi Ishibe, Ikuma Kato, Shoji Yamanaka, Satoshi Fujii, Itaru Endo, Yasushi Ichikawa. In colorectal cancer (CRC), neuroendocrine carcinoma (NEC) is contaminated in the cancer given a confirmed diagnosis of poorly differentiated adenocarcinoma (P-ad-ca) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5252.
Corrigendum to ‘Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial
Authors: B.G.M. Hughes, E. Munoz-Couselo, L. Mortier, Å. Bratland, R. Gutzmer, O. Roshdy, R. González Mendoza, J. Schachter, A. Arance, F. Grange, N. Meyer, A. Joshi, S. Billan, P. Zhang, B. Gumuscu, R.F. Swaby, J.-J. Grob
Journal: Annals of Oncology (2022)

The authors regret that a supplementary file for the protocol of the study was mistakenly missed at the time the article was published, although it was cited. The protocol has now been added to the supplementary files. The authors would like to apologise for any inconvenience caused. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trialAnnals of OncologyVol. 32Issue 10PreviewPembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). Full-Text PDF Open Access
Abstract 3548: Role of the cancer cell proteome and tumor microenvironment in the hyperprogression (HP) phenotype response to immune checkpoint blockade
Authors: Andrew George, Ilyas Sahin, Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2022)

Abstract Immune checkpoint blockade (ICB) immunotherapy strategies have yielded significant successes in recent years. Unfortunately, such treatments are not always successful. While tumor resistance to immunotherapy is often the reason, a subpopulation of patients treated with ICB show an acceleration in tumor growth rate, termed hyperprogressive disease (HPD) or hyperprogression (HP). Different studies have evaluated the incidence rate of HPD at 4% to 30%, though clear predictors have been elusive. An impediment to progress on investigating HPD has long been the lack of a reliable disease model. We recently reported a humanized mouse model of hyperprogression using mismatch repair deficient (MMR-d) p53-/- HCT-116 colorectal cancer cells implanted subcutaneously into athymic mice humanized with human CD8+ T-cell line TALL-104 and treated with anti-PD-1 Pembrolizumab. Flow cytometry was used to ensure the systemic establishment of the TALL-104 CD8+ human T-cells used to humanize the athymic mice and characterize immune tumor infiltration, which was not different between groups. Immunoperoxidase staining revealed increased expression of proliferation marker Ki67 within the HPD xenografts, supporting the finding that HPD tumors were exhibiting accelerated growth. Initial human cytokine analysis revealed a significant elevation in three cytokines (IFN-γ, TRAIL R2, and RANK L) and a significant decrease in four (CCL2, Chitinase 3-like 1, IL-4, and TNF-α). We attempted to mitigate HP through administration of anti-EGFR Panitumumab based on some clinical studies linking EGFR aberration to HPD but found worsened HPD in cotreated mice. We are conducting RNA sequencing to identify any changes in the RNAome of the HPD model, and immunoperoxidase analysis of resected tumor tissue for cytokine expression and cell death markers that may provide clues for accelerated growth within the HPD tumor microenvironment. Future studies will also focus on the interplay between Pembrolizumab and Panitumumab observed preliminarily to exacerbate the HPD with more comprehensive in vivo studies including of patient-derived xenotransplants. Citation Format: Andrew George, Ilyas Sahin, Shengliang Zhang, Wafik S. El-Deiry. Role of the cancer cell proteome and tumor microenvironment in the hyperprogression (HP) phenotype response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3548.
Abstract 5977: Discovery and preclinical validation of [11C]AZ3391: A first in class blood-brain barrier permeable, subtype selective PARP-1 PET radioligand
Authors: Peter Johnström, Jeffrey Johannes, Andy Pike, Zsolt Cselényi, Magnus Schou
Journal: Cancer Research (2022)

Abstract Positron emission tomography (PET) is a molecular imaging technique used to study the distribution of radiolabeled tracer molecules in vivo in a non-invasive fashion. We here report the discovery and preclinical validation of a novel PET tracer for PARP1. Its exquisite selectivity and high contrast in vivo opens up unique opportunities for exploring target engagement and relationships between drug exposure in plasma and PARP1 occupancy during clinical development of PARP1 inhibitors. AZ3391 was identified as a PET radioligand candidate from our medicinal chemistry program investigating novel PARP1 selective inhibitors and radiolabeled with carbon-11 (t1/2=20.4 min) for a series of in vitro and in vivo imaging experiments. Using in vitro autoradiography, dense binding of [11C]AZ3391 was observed in tissues known to be rich in PARP1 (eg tumour xenograft; NHP and human brain cerebellum). [11C]AZ3391 binding was completely abolished by the inclusion of a high concentration of Olaparib or AZD5305 in the incubate, thus demonstrating specific binding to PARP1 in vitro. Following intravenous injection of [11C]AZ3391 in non-human primates, high binding was observed in organs known to express PARP1, eg brain, spleen and bone marrow. The radioactivity in these organs could be blocked in a dose-dependent manner after pre-treatment with increasing doses of AZD9574 (up to 0.05 mg/kg), thus demonstrating specific binding to PARP1 in vivo. This set of preclinical data supports further development of [11C]AZ3391 as a tool to assess drug induced PARP1 engagement in patients. Citation Format: Peter Johnström, Jeffrey Johannes, Andy Pike, Zsolt Cselényi, Magnus Schou. Discovery and preclinical validation of [11C]AZ3391: A first in class blood-brain barrier permeable, subtype selective PARP-1 PET radioligand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5977.
Urinary Catheters for Inguinal Hernia Repair—The Challenges of Deimplementation of Routine Procedures
Authors: Martin Almquist
Journal: JAMA Surgery (2022)

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